The glucuronic acid derivatives of retinol and retinoic acid were first obtained as biliary metabolites of vitamin A (Dunagin et al. Science, 148: 86-87, 1965; Zachman et al. J. Lipid Res. 7: 3-9, 1966; Lippel and Olson, J. Lipid Res. 9: 580-586, 1968). The physiological significance of these glucuronides are not known yet, but recent findings of the presence of retinoyl glucuronide in the small intestine (Zile et al. J. Biol. Chem. 257: 3544-3550, 1982) and in the liver (McCormick et al. Biochemistry, 22: 3933-3940, 1984) suggest that the glucuronides of vitamin A might play some important role in the overall metabolism of vitamin A. Using very small quantities of natural retinoyl glucuronide, it was shown that the compound is biologically more active than retinoic acid in the vaginal smear assay (Sietsema and DeLuca, J. Nutr. 112: 1481-1489, 1982), and 30-100% as active as retinoic acid in the rat growth assay (Nath and Olson, J. Nutr. 93: 461-469, 1965).
Blindness resulting from vitamin A deficiency is a world-wide public health problem. Vitamin A deficiency occurs when body stores are exhausted and supply fails to meet the body's requirements, either because there is a dietary insufficiency, requirements are increased, or absorption and use are impaired. Vitamin A and all the known derivatives, except the glucuronides, are insoluble in water; they are lipid soluble and are absorbed and transported using a mechanism similar to the one used by lipids. Like all other exogenous and endogenous lipids that enter the gastrointestinal tract, vitamin A requires solubilization into mixed-micellar solutions before efficient absorption can occur (Underwood, in Retinoids, vol. 1, p. 281-392, ed. Sporn et al. Academic Press, Orlando, Fla., 1984). With the availability of a water-soluble derivative of vitamin A, the problem of absorption and transport of vitamin A is overcome.
Several retinoids, retinoic acid in particular, have been found very effective in the topical treatment and cure of xerophthalmia and corneal epithelial wounds (Ubels et al. Current Eye Res. 4: 1049-1057, 1985). These retinoids being water-insoluble pose significant problems in the formulation of a suitable vehicle for the clinical use. With the availability of water-soluble glucuronide derivatives, the formulation problem is overcome, since these derivatives could be applied as aqueous eye drops.
The first chemical synthesis of retinoyl .beta.-glucuronide was reported by us (Barua & Olson, J. Lipid Res. 26: 1277-1282, 1985), and involves a two-step procedure. Retinoyl fluoride was allowed first to react with 6,3-glucuronolactone to produce the 6,3-lactone of retinoyl glucuronic acid, which was then hydrolysed with very dilute alkali to give retinoyl .beta.-glucuronide. The present invention is an improvement over the two-step procedure.